Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000314.8 | MANE Select | 8515 nt | 846–2057 |
| NM_000314.7 | RefSeq Select | 8514 nt | 845–2056 |
| NM_000314.5 | Alternative | 8719 nt | 1032–2243 |
| NM_000314.4 | Alternative | 5572 nt | 1032–2243 |
| NM_000314.3 | Alternative | 3416 nt | 1032–2243 |
| NM_000314.6 | Alternative | 8718 nt | 1032–2243 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open"Present in ClinVar, however no clinical evidence available for this variant."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The PTEN E235* variant is a truncating mutation that results in a premature stop codon, leading to a loss of PTEN phosphatase function. Functional studies indicate that this variant reduces phosphatase activity, impairs the ability to negatively regulate the PI3K/AKT pathway, and increases genomic instability. These findings support a damaging effect of the PTEN E235* variant.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.24 | -14 bp |
| Donor Loss (DL) | 0.06 | 98 bp |
| Acceptor Gain (AG) | 0.06 | -212 bp |
| Donor Gain (DG) | 0.83 | -2 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to VCEP guidelines for PTEN, the rule for PVS1 Very Strong Strength is: 'Very Strong Use PTEN PVS1 decision tree.' The evidence for this variant shows: a truncating nonsense variant expected to cause loss of function, located outside the last exon of PTEN. Therefore, this criterion is applied at Very Strong strength because it fulfills the PTEN PVS1 decision tree for null variants resulting in LOF.
PS1 (Not Applied)
According to VCEP guidelines for PTEN, the rule for PS1 Strong Strength is: 'Same amino acid change as a previously established pathogenic variant regardless of nucleotide change OR different variant at same nucleotide position as a pathogenic splicing variant, where in silico models predict impact equal to or greater than the known pathogenic variant.' The evidence for this variant shows: no prior PTEN variant reported with the same amino acid change or position. Therefore, this criterion is not applied at Not Applied strength because the variant does not match an established pathogenic amino acid change.
PS2 (Not Applied)
According to VCEP guidelines for PTEN, the rule for PS2 Very Strong Strength is: 'Two proven OR four assumed OR one proven + two assumed de novo observations in a patient with the disease and no family history.' The evidence for this variant shows: no reported de novo occurrence data. Therefore, this criterion is not applied at Not Applied strength because de novo evidence is lacking.
PS3 (Moderate)
According to PTEN Pre-processing guidelines, the finding for PS3 is: 'Applied PS3_Moderate (Score -3.3226 < -1.11)'. The evidence for this variant shows: functional studies demonstrate reduced phosphatase activity with a score of -3.3226. Therefore, this criterion is applied at Moderate strength because the functional score meets the PTEN-specific PS3 Moderate threshold.
PS4 (Not Applied)
According to VCEP guidelines for PTEN, the rule for PS4 Strong Strength is: 'The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.' The evidence for this variant shows: no case-control or affected individual frequency data. Therefore, this criterion is not applied at Not Applied strength because prevalence data are unavailable.
PM1 (Not Applied)
According to VCEP guidelines for PTEN, the rule for PM1 Moderate Strength is: 'Located in a mutational hot spot and/or critical and well-established functional domain. Defined to include residues in catalytic motifs: 90-94, 123-130, 166-168.' The evidence for this variant shows: residue 235 is outside these defined hotspots. Therefore, this criterion is not applied at Not Applied strength because the variant is not in a PTEN hotspot or critical domain.
PM2 (Supporting)
According to VCEP guidelines for PTEN, the rule for PM2 Supporting Strength is: 'Absent in population Databases present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population.' The evidence for this variant shows: variant absent from gnomAD (MAF=0). Therefore, this criterion is applied at Supporting strength because the variant is absent from large population databases.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 Moderate Strength is: 'For recessive disorders, detected in trans with a pathogenic variant.' The evidence for this variant shows: PTEN is associated with dominant inheritance and no trans-occurrence data. Therefore, this criterion is not applied at Not Applied strength because PM3 is not relevant for a dominantly inherited gene.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 Moderate Strength is: 'Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.' The evidence for this variant shows: a nonsense variant leading to protein truncation, not an in-frame indel or stop-loss. Therefore, this criterion is not applied at Not Applied strength because the variant does not meet PM4 criteria.
PM5 (Not Applied)
According to VCEP guidelines for PTEN, the rule for PM5 Moderate Strength is: 'Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.' The evidence for this variant shows: the variant is a nonsense change, not a missense. Therefore, this criterion is not applied at Not Applied strength because PM5 applies only to missense variants.
PM6 (Not Applied)
According to VCEP guidelines for PTEN, the rule for PM6 Moderate Strength is: 'Assumed de novo, but without confirmation of paternity and maternity, in proband with the disease and no family history.' The evidence for this variant shows: no de novo data available. Therefore, this criterion is not applied at Not Applied strength because de novo status is not reported.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 Supporting Strength is: 'Co-segregation with disease in multiple affected family members.' The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied at Not Applied strength because segregation data are lacking.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 Supporting Strength is: 'Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.' The evidence for this variant shows: the variant is a nonsense change, not a missense. Therefore, this criterion is not applied at Not Applied strength because PP2 applies only to missense variants.
PP3 (Supporting)
According to VCEP guidelines for PTEN, the rule for PP3 Supporting Strength is: 'Multiple lines of computational evidence support a deleterious effect on the gene or gene product. Splicing variants: Concordance of SpliceAl and VarSeak.' The evidence for this variant shows: SpliceAI predicts a high splicing impact (0.83). Therefore, this criterion is applied at Supporting strength because computational predictions indicate a deleterious effect.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 Supporting Strength is: 'Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.' The evidence for this variant shows: no phenotype data provided. Therefore, this criterion is not applied at Not Applied strength because specific phenotype information is unavailable.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 Supporting Strength is: 'Reputable source reports variant as pathogenic.' The evidence for this variant shows: no ClinVar or other definitive pathogenic assertions. Therefore, this criterion is not applied at Not Applied strength because no authoritative external pathogenic classification is available.
BA1 (Not Applied)
According to VCEP guidelines for PTEN, the rule for BA1 Stand Alone Strength is: 'gnomAD Filtering allele frequency >0.00056 (0.056%).' The evidence for this variant shows: absent from gnomAD. Therefore, this criterion is not applied at Not Applied strength because allele frequency is below the BA1 threshold.
BS1 (Not Applied)
According to VCEP guidelines for PTEN, the rule for BS1 Strong Strength is: 'gnomAD Filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%).' The evidence for this variant shows: absent from gnomAD. Therefore, this criterion is not applied at Not Applied strength because allele frequency is below BS1 range.
BS2 (Not Applied)
According to VCEP guidelines for PTEN, the rule for BS2 Strong Strength is: 'Observed in the homozygous state in a healthy or PHTS-unaffected individual.' The evidence for this variant shows: no homozygous observations reported. Therefore, this criterion is not applied at Not Applied strength because BS2 evidence is lacking.
BS3 (Not Applied)
According to VCEP guidelines for PTEN, the rule for BS3 Strong Strength is: 'Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.' The evidence for this variant shows: functional studies indicate damaging effect. Therefore, this criterion is not applied at Not Applied strength because functional data support deleterious effect.
BS4 (Not Applied)
According to VCEP guidelines for PTEN, the rule for BS4 Strong Strength is: 'Lack of segregation in affected members of two or more families.' The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied at Not Applied strength because family segregation has not been assessed.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 Supporting Strength is: 'Missense variant in a gene for which primarily truncating variants are known mechanism of disease.' The evidence for this variant shows: the variant is truncating, not missense. Therefore, this criterion is not applied at Not Applied strength because BP1 applies only to missense variants.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 Supporting Strength is: 'Observed in trans with a pathogenic variant in a dominant gene.' The evidence for this variant shows: no data on cis/trans configuration. Therefore, this criterion is not applied at Not Applied strength because phase information is not available.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 Supporting Strength is: 'In-frame deletions/insertions in a repetitive region without a known function.' The evidence for this variant shows: a nonsense variant, not in-frame. Therefore, this criterion is not applied at Not Applied strength because BP3 applies only to in-frame indels.
BP4 (Not Applied)
According to VCEP guidelines for PTEN, the rule for BP4 Supporting Strength is: 'Multiple lines of computational evidence suggest no impact on gene or gene product.' The evidence for this variant shows: mixed computational predictions and SpliceAI supports impact. Therefore, this criterion is not applied at Not Applied strength because computational evidence does not support benign effect.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 Supporting Strength is: 'Variant found in a case with an alternate molecular basis for disease.' The evidence for this variant shows: no alternate molecular diagnosis reported. Therefore, this criterion is not applied at Not Applied strength because no alternate etiology is documented.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 Supporting Strength is: 'Reputable source reports variant as benign.' The evidence for this variant shows: no such reports. Therefore, this criterion is not applied at Not Applied strength because no authoritative benign assertion exists.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 Supporting Strength is: 'Synonymous or intronic variant with no predicted splicing impact.' The evidence for this variant shows: the variant is a nonsense change, not synonymous/intronic. Therefore, this criterion is not applied at Not Applied strength because BP7 applies only to silent/intronic variants.